Using genetic knockout approaches in mice, the Kulkarni laboratory has demonstrated that the beta-cell is an insulin sensitive tissue and that insulin resistance in beta-cells creates a first phase insulin secretory defect similar to that of humans with type 2 diabetes. Kulkarni and colleagues have defined how these early signals link to other signalling pathways, including control of growth and apoptosis; changes in calcium flux and insulin secretion; and the role of members of the Bcl family in control of beta-cell apoptosis. Together, this seminal work has helped reshape our view of the pathogenesis of type 2 diabetes integrating insulin action and insulin resistance in the beta-cell with that in peripheral tissues in creation of the full spectrum of abnormalities in glucose homeostasis observed in this disorder. In recent work the Kulkarni laboratory has focused on understanding the link between the role of neuropeptides that control appetite on the one hand and regulat islet function funcstion and growth on the other. The studies on leptin and melanocyte concentrating hormone (MCH) indicate a complex interplay forming a hypothalamic/islet axis in the regulation of glucose homeostasis.